2-amino-3-carbethoxyamino-6-(4-fluoro-benzylamino)-pyridine (“Flupirtine”) of the following formula (1):
is a centrally active non-opioid analgesic which does not cause any addiction or tolerance development. It is also a muscle-relaxant.
Flupirtine has a unique spectrum of pharmacological activity. It is used in the treatment and prevention of acute and chronic pain including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dental pain and the pain associated with degenerative and inflammatory joint disease.
Flupirtine is also used in the treatment and prevention of muscular tension, muscle spasm and muscle stiffness. It is particularly useful in the treatment of back pain. Additionally, flupirtine also exerts potent cyto- and neuroprotective effects and has utility in the treatment and prevention of neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt-Jakob disease including classical and new-variant types and Batten disease. Flupirtine also has utility in the treatment and prevention of diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa. Flupirtine also has utility in the treatment and prevention of myocardial ischemia and infarction, cerebral ischemia and infarction, shock, tinnitus and hepatitis.
Flupirtine is commonly used in the form of pharmaceutically acceptable acid addition salts. Commercially, flupirtine is available as its maleate addition salt under the trademark Katadolon®.
There are two known polymorphs of flupirtine maleate, designated in the art as flupirtine maleate A and B. European patent EP 0 977 736 discloses pure flupirtine maleate crystalline form A and a process for its preparation. Flupirtine and mixtures of flupirtine maleate polymorphs A and B and pure polymorph B can be synthesised according to DE 3133519.
Other known flupirtine salts are flupirtine chloride, reported in German patent DE 1 795 858, and flupirtine gluconate, reported in European patent EP 0 160 865. WO 2004/112754 discloses several acid addition salts of flupirtine and their use in lyophilisates for parenteral solutions. For example, the flupirtine gluconate acid addition salt was prepared by lyophilisation and obtained in amorphous form.
Polymorphs A and B of flupirtine maleate are both characterized by an acicular morphology. The extremely fine needle structure of flupirtine maleate poses difficulties in the formulation process as is, for example, reported in EP 1 795 186. In particular, the acicular structure poses difficulties in the development of controlled release formulations of flupirtine as is described in patents EP 0 615 754 and EP 1 795 186. Furthermore, due to the acicular morphology, polymorphs A and B of flupirtine maleate have a very low bulk density and poor flowability causing difficulties in the formulation process. As a consequence, dosing of flupirtine maleate is difficult and the reproducibility of the formulation process is poor. These characteristics of flupirtine maleate necessitate a costly additional mechanical treatment of the drug substance for proper further processing.
In addition, flupirtine maleate is sensitive to oxygen and poorly soluble in water. It is also known to form an isopropanol solvate, as reported in “Polymorphism and desolvation of flupirtine maleate”, European Journal of Pharmaceutics and Biopharmaceutics 46 (1998) 329-337.
It is the object of the present invention to provide acid addition salts of flupirtine which are characterized by an improved balanced mix of solubility, oxidation stability and morphology, i.e., possessing a less acicular morphology. Furthermore, it is also the object of the present invention to provide pharmaceutical compositions comprising said flupirtine-addition salts as active ingredient, to processes for producing said salts and pharmaceutical compositions, and to therapeutic uses thereof.